Preparation of beta-isothiourea propionic acids



Patented July 5, 1949 PREPARATION OF BETA-ISOTHIOUREA PROPIONIC ACIDS Thomas L. Gresham and Forrest W. Shaver, Akron, Ohio, assignors to The B. F. Goodrich Company, New York, N. Y. a corporation of New York I No Drawing. Application October 5, 1945,

, Serial No. 620,661

I 2 Claims. (Cl. 260--534) This invention relates to the preparation oi nitrogenand sulfur-containing beta-substituted carboxylic acids, particularly propionic acids, and is especially concerned with the preparation of such compounds by the reaction of beta-lactones with certain nitrogenand sulfur-containing compounds such as the thioureas.

It is disclosed in U. S. Patent 2,356,459 to Frederick E. Kiing that beta-lactones, that is lactones or inner esters of beta-hydroxy carboxylic acids may be obtained in good yields by the reactionof a ketene with an aldehyde or ketone. In this manner beta-propiolactone (also called hydracrylic acid lactone) which has the structure is economically obtained from ketene and formaldehyde.

We have now discovered that beta-propiolactone, and also the other beta-lactones, will react with nitrogen and sulfur containing organic compounds having a nitrogen atom and a sulfur atom satisfying three valences of the same carbon atom and having at least one hydrogen atom attached to at least one of the said nitrogen and sulfur atoms, to produce in high yields beta-substituted carboxylic acids in which a thio linkage, -S-, is attached on the one hand to a carbon atom in turn attached by a double bond to a nitrogen atom and on the other hand to a carbon atom in beta position to a carboxyl group. p

The nitrogen and sulfur containing compound may be, in accordance with the above definition,

' one containing the characteristic structure s ,or 'it maybe a tautomeric form of such a compound having the characteristic structure C-SH In either event the compound reacts in the latter tautomeric form with the beta-lactone in accordance with the following equation: 3H \..CC=

I o f Beta-lactone V Sulfur Betasubstituted carboxylic laid silacid coi taim 111g compound the disconnected valences being attached to hydrogen atoms, or to any of the other groupings capable of covalently linking to carbon or nitrogen as the case may be.

No special conditions for the reaction are necessary, the reaction proceeding whenever it is possible to bring the reactants into eifective contact with one another. This is ordinarily accomplished by the use of a solvent for the reactants, polar solvents being preferred. Since many of the nitrogen and sulfur-containing compounds and many beta-lactones are soluble in water, the use of water, as the solvent for the reactants is an especially preferred procedure, In this event the beta-substituted product, being generally insoluble in water, is precipitated during the reaction and is thus readily separated from the reaction medium. Other polar solvents which dissolve the reactants such as alcohols, organic acids, organic nitriles, and the like, however, may also be used. The temperature at which the reaction is efictecl is not critical but is preferably from 0 to 0., more preferably from 0 to 50 C. Proportions of reactants may be varied widely using an excess of either of the reactants if desired, but in general the use of substantially equi- Example 1 An aqueous solution of thiourea is prepared by dissolving 76 parts by weight of thiourea in 300 parts by weight of water, heating to assist dissolution if necessary. The solution is then cooled to 20 C. and 72 parts by weight of beta-propiolactone are'slowly added with constant stirring while the temperature of the solution is between about 20 and 30 C. During addition of the betalactone aprecipitate separates from solution and after the addition the thick reaction product is stirred for about an hour. The precipitate is filtered and recrystallized from hot water whereupon crystals of a hydrate of ,beta-isothiourea propionic acid are obtained. When this hydrate is heated it loses water and a white powder consisting of beta-isothiourea propionic acid (which may also be called S-beta-carboxyethyl isothiourea) (M. P. -171" C.) .is produced in quantitative yield. The product possesses the structure:

When the product obtained beta-isothiourea propionic acid) is refluxed with sodium hydroxide and the solution then acidified, thiohydracrylic acid (beta-mercapto-propionic acid) is obtained in substantially quantitative yield. Hence the reaction of the above example may be utilized as a means of producing thiohydracrylic acid from beta-propiolactone.

Other water-soluble thiourea compounds (thiocarbamides) may be substituted for thiourea in the above example and similar beta-substituted propionic acids thereby secured. For example, methyl thiourea, N,N'-diethyl thiourea, phenyl thiourea, acetyl thiourea glycollyl thiourea (i. e., thiohydantoin), malonyl thiourea (i. e., thiobarbituric acid), thiohydantoic acid meric forms of any of the above-mentioned comcarbamyl thiourea (i. e. thiobiuret) guanylthiourea, thioallantoin, trithiocyanuric acid and other compounds of the general formula \N--CN H R s R wherein at least one It represents hydrogen and the remainder represent organic radicals, which may or may not be connected to each other to form a cyclic structure, may all be reacted with beta-propiolactone in aqueous solution to form crystalline beta-substituted propionic acids. In

addition, thioureas which are not appreciably soluble in water such as N,N'-diphenyl-thiourea (thiocarbanilide), N,N-diphenyl thiourea, symdi-o-tolyl thiourea, benzyl thiourea and the like may also be reacted with the beta-lactone by employing ethyl alcohol or some other solvent for .the reactants in place of water.

It is also within the scope of this react numerous other sulfur and nitrogen containing organic compounds, preferably Watersoluble compounds, which possess one of the structures with beta-lactones, and thereby to obtain other beta-substituted carboxylic acids. Thus, thioacetamide and thiobenzamide and their homologs and N-substituted derivatives have only one hydrogen replaced such as thio-acetanilide, and other compounds of the formula where R1 is an organic radical having its connecting valence on a carbon atom and R2 is hydrogen or such an organic radical, including thio oxamic acid,

and its esters, and the like may be reacted with beta-lactones to produce beta-substituted carboxylic acids. Other nitrogen and sulfur compounds of the type described include thio-carbazides, thiosemicarbazides and thiuram sulfides and disulfides of the formula where at least one R is hydrogen and the remainder are organic radicals, and n is 1 or 2. Tautoinvention to -stituted carboxylic' acid compounds.

pounds, which differ only in that the structure is changed to the structure may also be used.

Since ammonium dithiocarbamate and similar compounds also contain the structure, their reaction with beta-lactones is also included in the broad scope of this invention, but is more specifically disclosed and claimed'in the copending application of Thomas L. Gresham and Jacob Eden Jansen, Ser. No. 620,663, filed October 5, 1945. Similarly, the reaction of betalactones with certain nitrogen containing heterocyclic mercaptans such as the Z-mercaptothiazoles and Z-mercaptothiazolines, which contain the structure, is included within the broad scope of this invention but is more specifically disclosed and claimed in the copending application of Jacob Eden Jansen and Roger A, Mathes, Ser. No. 620,662, filed October 5, 1945.

. Although beta-propiolactone, the simplest possible beta-lactone, is the preferred beta-lactone for use in this invention because of its low cost, its solubility in water and the ease with which the reaction is carried out, the homologs of beta propiolactone, that is, other saturated aliphatic beta-lactones such as beta-butyrolactone, betaisobutyrolactone, beta-valerolactone, beta-isovalerolactone, beta-n-caprolactone, alpha-ethylbeta-propiolactone, alpha-isopropyl-beta-propio-' wherein R is hydrogen or an unreactive hydrocarbon group (i. e., a hydrocarbon group free from aliphatic unsaturation) and may be prepared in the manner described in the above-mentioned Kiing patent. Still other known betalactones include lactones of unsaturated beta.- hydroxy carboxylic acids, mono-beta lactones-oi dicarboxylic acids and dilaqtoues of dicarboxylic oxygen atoms. In addition to these compounds other compounds containing the structure but having the valences on the alpha and beta carbons attached to groups containing elements other than or in addition to carbon and hydrogen such as oxygen, nitrogen, sulfur and halogen, whether in essentially unreactive structure such as nitro groups and ether linkages or in radicals containing reactive hydrogen such as amino and hydroxy, are also beta-lactones and hence are included within the generic class of beta-lactones. Examples of such latter compounds are alpha or beta-nitrophenyl-beta-propiolactone; beta (0- nitro-m-chlorophenyl) -beta.-propiolactone beta- (O-nitro-m-methoxyphenyl) -beta-propiolactone; alpha hydroxy beta-phenyl-beta-propiolactone and alpha bromo beta, beta dimethyl-betapropiolactone-alpha-carboxylic acid.

Thus, any of the generic class or beta-lactones may be used in the practice of this invention. when the reaction is carried out in aqueous solution, as in preferred, beta-lactones which are soluble in water (those beta-lactones containing no more than about six carbon atoms possess this property) are of course used.

The nitrogen and sulfur containing beta-substituted carboxyllc acid compounds obtained by the reaction described are generally solid organic compounds which are useful as intermediates in the preparation of other compounds and for various other purposes. As mentioned above, they may be hydrolyzed to yield beta-mercapto carboxylic acids. In many instances they may be cyclicized to produce heterocyclic nitrogen and sulfur containing compounds.

Numerous other modifications and variations in the method of effecting the reaction and in the materials therein used will be obvious to those skilled in the art and are within the spirit and scope of the invention as defined in the appended claims.

We claim:

1. The method of preparing beta-isothiourea propionic acid which comprises reacting in aqueous solution beta-propiolactone and thiourea.

2. The method which comprises reacting a saturated aliphatic beta-lactone with thiourea and recovering the beta-isothiourea saturated aliphatic monocarboxylic acid thus formed.

THOMAS L. GRESHAM. FORREST W. SHAVER.

REFERENCES CITED The following references are of record in the die of this patent:

FOREIGN PATENTS Country Date France Sept. 1, 1939 OTHER REFEQENCES Number 

